Brain gliomas progress as function of crucial gene is lost

For the first time, researchers are characterizing the molecular processes that turn brain cancer deadly, and their work may result in a diagnostic test that can predict patient survival.

The research, by scientists at The University of Texas M. D. Anderson Cancer Center demonstrates that degree of loss of a crucial tumor suppressor gene, the AP-2( transcription factor, correlates with progression of different human gliomas.

For example, researchers found that normal brain tissue, as well as grade II gliomas, maintained expression of AP-2(, whereas 96 percent of grade III glioma, and almost 99 percent of grade IV glioma had lost AP-2(.

“Although previous molecular markers have been identified in malignant gliomas, none have exhibited such a strong correlation with progression, indicating the pivotal role of this gene,” says Amy Heimberger, M.D., assistant professor in the Department of Neurosurgery.

The findings one day may be clinically important, says Eric McGary, M.D., Ph.D., a clinical fellow.

If validated through further study, the results can help scientists devise a diagnostic test to check for loss of function of the AP-2( gene, which can help doctors and patients know about treatment options. “No such test exists like that now,” he says. Dr. Heimberger is following the long-term survival of patients within the various grades of gliomas to determine if loss of the AP-2( confers a more serious prognosis.

McGary led the effort to characterize how cancer develops when the AP-2( gene, which normally protects against cancer development, is lost. They have found that other tumors such as melanoma become increasingly deadly when the gene is no longer active, and have described its role in breast and prostate cancer as well.

The AP-2( transcription factor controls the expression of many genes, including c-Kit, which regulates cellular proliferation and differentiation, MUC18, an adhesion molecule involved in angiogenesis, and MMP2, which is involved in invasion. When AP-2( is lost, less c-Kit, but more MUC18 and MMP2 are produced, resulting in an increased potential of the cell to grow and divide uncontrollably.

“As such, AP-2( acts as a tumor suppressor gene,” says Menashe Bar-Eli, PhD, professor in the Division of Cancer Medicine and a senior member of the research team.

Looking at tumor samples taken from 279 patients with different kinds of brain cancer, the research team used a tissue array constructed by Dr. Gregory Fuller, associate professor in the Department of Pathology, to look for AP-2( gene expression.

In addition to their findings of different stages of gliomas, they found that 21.5 percent of oligodendrogliomas did not express AP-2(, but this increased to 66 percent in cases of anaplastic oligodendrogliomas.

The team also looked at glioblastomas, which are the most common malignant brain tumors in adults and are the most resistant and deadly of all brain cancers to treat. They found that none of the four different glioblastoma cell lines they tested expressed any detectable levels of AP-2(.

“The discovery of the ubiquitous loss of AP-2( in high-grade malignant gliomas provides a unique target for new therapies aimed at restoring the function of that gene,” says Heimberger. “We are already looking at trying to replace AP-2( function in animal models with gene therapy in order to slow down growth of the tumor,” McGary added.